The central nervous system is peculiar among mammalian organs in that differentiated neurones are practically incapable of regeneration. Permanent loss of function is a likely outcome of a sufficiently severe injury to the brain. It is particularly sad to meet children whose brains have been damaged by hypoxia during a difficult birth. There is therefore a need for means to protect cells of the central nervous system (also including the glial cells) from death after an injury.
After asphyxial, traumatic, toxic, infectious, degenerative, metabolic, ischaemic or hypoxia insults to the central nervous system (CNS) of man or other mammals a certain degree of damage in several different cell types may result. For example periventricular leucomalacia, a lesion which affects the periventricular oligodendrocytes is generally considered to be a consequence of hypoxic ischemic injury to the developing preterm brain (Bejar et al., Am. J. Obstet. Gynecol., 159:357-363 (1988); Sinha et al., Arch. Dis. Child., 65:1017-1020 (1990); Young et al., Ann. Neurol., 12:445-448 (1982)). Damage to the CNS by trauma, asphyxia, ischemia, toxins or infection is frequent and may cause sensory, motor or cognitive deficits. Glial cells which are non-neuronal cells in the CNS are necessary for normal CNS function. Infarcts are a principal component of some hypoxia ischemic induced damage and loss of glial cells is an essential component of infarction. There appears to be a kind of "delayed injury process" in which apparently "self-destructive" neural activity occurs some time after an injury; attempts to control this activity appear able to alleviate the effects of this delayed injury process.
Diseases of the CNS also may cause loss of specific population of cells. For example multiple sclerosis is associated with loss of myelin and oligodendrocytes, similarly Parkinson's disease is associated with loss of dopaminergic neurons. Some situations in which CNS injury or disease can lead to predominant loss of neurons and/or other cell types include: perinatal asphyxia associated with fetal distress such as following abruption, cord occlusion or associated with intrauterine growth retardation; perinatal asphyxia associated with failure of adequate resuscitation or respiration; severe CNS insults associated with near-miss drowning, near-miss cot death, carbon monoxide inhalation, ammonia or other gaseous intoxication, cardiac arrest, collapse, coma, meningitis, hypoglycaemia and status epilepticus; episodes of cerebral asphyxia associated with coronary bypass surgery; cerebral anoxia or ischemia associated with stroke, hypotensive episodes and hypertensive crises; and cerebral trauma.
There are many other instances in which CNS injury or disease can cause damage to cells of the CNS. It is desirable to treat the injury in these instances. Also, it is desirable to prevent or reduce the amount of CNS damage which may be suffered as a result of induced cerebral asphyxia in situations such as cardiac bypass surgery.
We have previously shown (in New Zealand Patent Application No. 239211--"IGF-1 to improve neural outcome", the contents of which are hereby incorporated by way of reference) that the growth factor called insulin-like growth factor 1 (IGF-1) has an unanticipated action, namely to prevent brain cells from dying after an asphyxial or ischemic brain insult (Gluckman et al Biochem Biophys Res Commun 182:593-599 1992). Because insulin also has a neuroprotective action (Voll et al Neurology 41:423-428 (1991)) and insulin and IGF-1 can both bind to the IGF-1 receptor, it was generally assumed that this brain rescue mode of action of IGF-1 was mediated via the IGF-1 receptor (Guan et al J. Cereb. Blood Flow Metab. 13:609-616 (1993)).
It is known that IGF-1 can be modified by proteolytic cleavage in nervous tissue to des 1-3N IGF-1, that is IGF-1 missing the 3 amino acids from the amino terminal of the molecule, and hence after cleavage there is also a 3 amino acid peptide gly-pro-glu which is the N terminal tripeptide. This tripeptide is also termed GPE. As des 1-3N IGF-1 also binds to the IGF-1 receptor and GPE does not, the GPE was thought to be of no significance to the neuronal rescue action of IGF-1.
Our previous work had shown that the brain increases its production of IGF-1 following brain injury by hypoxia-ischemia and that in addition it increases the synthesis of two specific binding proteins. IGF binding protein-2 (IGFBP-2) and IGF binding protein-3 (IGFBP-3) (Gluckman et al Biochem Biophys Res Commun 182:593-599 (1992) and Klemp et al Brain Res 18:55-61 (1992). These were hypothesised to attract the IGF-1 into the region of injury to reach concentrations necessary for neuronal rescue. For this reason IGF-1 was anticipated to be more potent given at a site distant from the injury than des 1-3 N IGF-1 which does not bind well to the binding proteins. This was indeed the case--1-3 N IGF-1 was not significantly active as a neuronal rescue agent at a dose equivalent to that at which IGF-1 shows neuronal rescue activity. Thus the prior art pointed to activity at the IGF-1 receptor as the mode of neuronal rescue achieved with IGF-1.
To date, there has been no enabling reference in the prior art to the manipulation of the cleaved tripeptide GPE itself to prevent or treat CNS injury or disease leading to CNS damage in vivo.
One disease which leads to CNS damage in vivo is Parkinson's disease. Parkinson's disease is the second most prevalent neurodegenerative disorder after Alzheimer's . It is a chronic and progressive motor system disorder and is distinguished by a tremor at rest, muscular rigidity, a slowness of movement initiation and movement execution and a mask-like appearance to the face.
The cause of this disease is unknown but the symptoms are a consequence of an 80% or greater loss of the dopaminergic neurons (which produce dopamine) in the pars compacta region of the substantia nigra.